Age-related hearing loss (presbycusis) is the most common sensory deficit in human populations; about 1 in 3 adults older than 60 suffer from a significant hearing loss. The genetic basis of presbycusis is poorly understood because of the extreme difficulty in studying such a late-onset genetically complex disorder. The laboratory mouse provides promising models for studying human presbycusis because age-related hearing loss (AHL) is common in inbred mouse strains and mice are more amenable to genetic analyses. We have shown that a gene on Chromosome 10 (Ahl) is a major susceptibility factor for AHL in more than 10 inbred strains of mice and that a mitochondrial mutation in A/J mice exacerbates this hearing loss. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic studies of AHL in mice will add significantly to our understanding of presbycusis in humans. Our specific aims are (1) to identify the Chr 10 Ahl gene, first analyzing Cdh23, a co-localized gene that is mutated in deaf waltzer mice, by genetic complementation tests for allelism and by gene rescue experiments; (2) to refine the map position of a newly discovered AHL locus on Chr 5 (Ahl2) and test candidate genes in the region; (3) to map additional loci that contribute to AHL and analyze defined locus combinations on uniform strain backgrounds; and (4) to test homologs of mouse AHL loci for their potential role in human presbycusis by analyses of linkage disequilibrium and DNA alterations in patients and matched controls. The long-term objectives of this research are to provide a better understanding of the molecular mechanisms and pathophysiology of AHL that could contribute to the development of diagnostics, preventive interventions, and therapies for human presbycusis.